The overall aim of this proposal is to determine the relation of severity of depressive symptoms to the inflammatory process implicated in atherogenesis. Epidemiological studies indicate that severity of depressive symptoms is a significant predictor of cardiovascular disease risk. At this time, pathophysiological mechanisms underlying this link are incompletely defined. A central characteristic of the pathogenesis of atherosclerosis is the proinflammatory response of blood monocytes. This response is characterized by the increased expression of various inflammatory cytokines and cell adhesion molecules. We hypothesized that severity of depressive symptoms is associated with greater basal expression of cytokines and cell adhesion molecules on blood monocytes. We also hypothesized that, in persons with depressive symptoms, stress-induced changes in monocyte markers are positively associated with arousal of negative affects, stress-induced-neuroendocrine responses, and fasting lipids. To test these hypotheses, we propose to conduct a study in 300 healthy, non-smoking individuals, 150 men and 150 premenopausal women. We propose the following specific aims: 1) To investigate the degree to which severity of depressive symptoms is associated with greater basal expression of cytokines and adhesion molecules on blood monocytes; 2) To investigate the degree to which stress-induced changes in the expression of monocyte cytokines and cell adhesion molecules are associated with stress-induced emotional arousal as a function of severity of depressive symptoms; 3) To investigate the degree to which stress-induced changes in the expression of monocyte cytokines and cell adhesion molecules are associated with stress-induced catecholamine and cortisol responses as a function of severity of depressive symptoms; and 4) To investigate the degree to which stress-induced changes in the expression of monocyte cytokines and cell adhesion molecules are associated with fasting lipids as a function of severity of depressive symptoms. In accomplishing these aims, we will also explore the potential moderating effects of gender, as well as ovarian hormones, on the above relationships. If we are successful, we will provide empirical evidence to support the hypothesis that severity of depressive symptoms is associated with proinflammatory cellular activities linked to human atherosclerosis.